Alzheimer's disease [AD] is characterized by A amyloid deposits in the form of extracellular amyloid (A) plaques and tau protein aggregates in the form of intracellular neurofibrillary tangles (NFT). Soluble oligomeric forms of A and tau are the chief mediators of cytotoxicity in AD. Preclinical studies in transgenic mouse models have shown great efficacy of A targeting immunotherapy in the prevention of AD but clinical trials have so far failed to show benefits. We plan to test the hypothesis that for therapy to be effective the concurrent targeting of both A and tau related pathology is essential. Our novel active immunization approach uses a polymerized peptide derived from the carboxyl terminus of the British amyloidosis (ABri) peptide prepared by the use of glutaraldehyde as a cross linker, that results in a stabilized, predominately sheet oligomeric form that does not form fibrils, which we term pBri. We showed that via conformational mimicry, the pBri peptide, in its stabilized oligomeric form, can initiate a conformation selective immune response, which is specific to pathological aggregated/oligomeric conformers of phosphorylated tau and A. In the last funding period we have also shown that stimulation of innate immunity via TLR9 can reduce plaques and tau pathology in Tg2576 and 3xTg mice.
The specific aims are: 1) Test conformation targeted active immunization with pBri in htau/PS1 Tg and Tg4510 mice with extensive NFT pathology, as well as in a model of Lewy body pathology (tTA/A53Ta-syn) in order to determine if our novel active immunization approach is effective against tau and a- synuclein related pathology. 2) Characterize our panel of monoclonal anti-pathological conformation antibodies using human tissue, Western blots, laser capture microdissection and surface plasmon resonance measurements. The best mAb will be tested in Tg mouse models. 3) We will determine if our method of stimulating innate immunity via TLR9 with CpG is effective at ameliorating vascular amyloid in TgSwDI mice and tau pathology in Tg4510 mice. These planned studies will provide essential data on three therapeutic approaches that concurrently target A and tau pathology prior to potential testing in humans.

Public Health Relevance

The central hypothesis to be tested in this proposal is that specific immunological targeting of both A and tau oligomer related pathology concurrently will result in an effective therapeutic approach for Alzheimer's disease (AD). We plan to test both active and passive immunization to the shared pathological conformation of tau and A oligomers, and we will determine if innate immunity stimulation via Toll-like receptor 9 can reduce both vascular A deposits and tau related pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073502-09
Application #
9487037
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Corriveau, Roderick A
Project Start
2010-09-01
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York University
Department
Neurology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Goñi, Fernando; Martá-Ariza, Mitchell; Herline, Krystal et al. (2018) Anti-?-sheet conformation monoclonal antibody reduces tau and A? oligomer pathology in an Alzheimer's disease model. Alzheimers Res Ther 10:10
Ramos-Cejudo, Jaime; Wisniewski, Thomas; Marmar, Charles et al. (2018) Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link. EBioMedicine 28:21-30
Drummond, Eleanor; Nayak, Shruti; Pires, Geoffrey et al. (2018) Isolation of Amyloid Plaques and Neurofibrillary Tangles from Archived Alzheimer's Disease Tissue Using Laser-Capture Microdissection for Downstream Proteomics. Methods Mol Biol 1723:319-334
Herline, Krystal; Prelli, Frances; Mehta, Pankaj et al. (2018) Immunotherapy to improve cognition and reduce pathological species in an Alzheimer's disease mouse model. Alzheimers Res Ther 10:54
Solesio, María E; Peixoto, Pablo M; Debure, Ludovic et al. (2018) Carbonic anhydrase inhibition selectively prevents amyloid ? neurovascular mitochondrial toxicity. Aging Cell :e12787
Goñi, Fernando; Martá-Ariza, Mitchell; Peyser, Daniel et al. (2017) Production of Monoclonal Antibodies to Pathologic ?-sheet Oligomeric Conformers in Neurodegenerative Diseases. Sci Rep 7:9881
Nwabuobi, Lynda Adaobi; Pellinen, Jacob Christian; Wisniewski, Thomas Mark (2017) Thymoma-associated panencephalitis: a newly emerging paraneoplastic neurologic syndrome. Neuroimmunol Neuroinflamm 4:117-123
Wegiel, Jerzy; Flory, Michael; Kuchna, Izabela et al. (2017) Multiregional Age-Associated Reduction of Brain Neuronal Reserve Without Association With Neurofibrillary Degeneration or ?-Amyloidosis. J Neuropathol Exp Neurol 76:439-457
Drummond, Eleanor; Wisniewski, Thomas (2017) Alzheimer's disease: experimental models and reality. Acta Neuropathol 133:155-175
Scholtzova, Henrieta; Do, Eileen; Dhakal, Shleshma et al. (2017) Innate Immunity Stimulation via Toll-Like Receptor 9 Ameliorates Vascular Amyloid Pathology in Tg-SwDI Mice with Associated Cognitive Benefits. J Neurosci 37:936-959

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